LCZ696: The NEP inhibitor prodrug sacubitril (AHU377, (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester, also named N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester; IUPAC name 4-{[(1S,3R)-1-([1,1′-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoic acid) together with valsartan, a known angiotensin receptor blocker (ARB), forms a sodium salt hydrate complex, known as LCZ696, comprising the anionic forms of sacubitril and valsartan, sodium cations and water molecules in the molar ratio of 1:1:3:2.5, respectively (ratio of 6:6:18:15 in the asymmetric unit cell of the solid state crystal), and which is schematically present in the following formula:

Said complex is also referred to by the following chemical names: Trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl {2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemi-pentahydrate or Octadecasodium hexakis(4-{[(1S,3R)-1-([1,1′-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate) hexakis(N-pentanoyl-N-{[2′-(1H-tetrazol-1-id-5-yl)[1,1′-biphenyl]-4-yl]methyl}-L-valinate)—water ( 1/15) (IUPAC nomenclature).
Ingestion of LCZ696 results in systemic exposure to sacubitril, the neprilysin (neutral endopeptidase 24.11, NEP) inhibitor (NEPi) prodrug which is converted to the active form LBQ657 (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionyl amino)-2-methyl-pentanoic acid), and valsartan providing inhibition of the angiotensin II type 1 (AT1) receptor, in a 1:1 molar ratio.
Combinations of sacubitril and valsartan, and in particular LCZ696 and formulations thereof, have been previously disclosed in WO 2003/059345, WO 2007/056546, and WO 2009/061713, which are herein incorporated by reference.
Mode of action: Neprilysin inhibition leads to enhanced levels of the physiologically active natriuretic peptides (NPs), including atrial natriuretic peptide (ANP). NPs mediate their cardiovascular effects through activation of the natriuretic peptide receptor A (NPR-A) and their second messenger cyclic GMP (cGMP), resulting in potent vasodilation, natriuresis, diuresis, inhibition of the renin angiotensin aldosterone system (RAAS) by reducing renin and aldosterone release, reduced sympathetic drive, and antiproliferative and antihypertrophic effects on vascular endothelium and smooth muscle cells. The angiotensin receptor blocker (ARB) component provides AT1 receptor antagonism, preventing the deleterious effects of angiotensin II and thereby lowering peripheral vascular resistance. By delivering dual and potentially complementary beneficial effects, LCZ696 may offer clinical benefits to patients with cardiovascular and renal disease.
Various uses of combinations of sacubitril and valsartan, and in particular LCZ696, for the treatment of patients with various cardiovascular and/or renal diseases have been described in e.g. WO 2003/059345, WO 2007/056546, WO 2012/027237, WO 2014/029848, WO 2015/030711, and WO 2015/028941.
In particular, neprilysin (NEP) inhibition with chronic oral administration of LCZ696 can promote the endogenous capacity of the body to compensate for Heart Failure (HF) exacerbations by potentiating the activity of natriuretic peptides secreted by the heart in response to cardiac stress and increased intravascular volume. LCZ696, unlike any other therapy for HF, provides concomitant inhibition of NEP and the angiotensin type 1 (AT1) receptor. The resulting increase in natriuretic peptide (NP) activity due to NEP inhibition and AT1 receptor blockade through renin-angiotensin-aldosterone system (RAAS) inhibition have complementary effects on the cardiovascular (CV) system that benefit HF patients.
In PARADIGM-HF (CLCZ696B2314; N=8442), the pivotal Phase 3 study in adult patients with HF with reduced ejection fraction (HFrEF), LCZ696 was superior to enalapril (the standard of care) in delaying time to first occurrence of composite endpoint of CV death or HF hospitalization, with a 20% relative risk reduction (RRR) (p=0.0000002). In addition, LCZ696 was superior to enalapril in delaying time to CV death with a 20% RRR p=0.00004) and in delaying time to first HF hospitalization with 21% RRR (p=0.00004). PARADIGM-HF also showed that LCZ696 is generally safe and well tolerated in adult patients with HF (McMurray et al, 2014).
LCZ696 is now considered for use in children as an alternative to currently available therapies for cardiovascular diseases such as heart failure (HF).
Congenital heart disease and cardiomyopathy are the two most common causes of pediatric HF. An incidence of 10.4% has been reported in HF patients <16 years with congenital or acquired heart disease and a 2 to 7.7/100,000 incidence of HF in the general pediatric population. The highest incidence of HF occurs in infants and children between 0 and 4 years of age. A second peak of pediatric HF, due mainly to cardiomyopathy and unrepairable or palliative repair of congenital heart defects causes, appears between ages 10 and 18. It is estimated that between 12,000 to 35,000 children below age 19 are diagnosed with pediatric HF in the United States each year. The largest HF burden comes from children born with congenital malformations. Congenital heart disease occurs in approximately 8 per 1,000 live births of which 1-2 per 1,000 develop HF. A wide variety of congenital abnormalities may be present. Most of these children are diagnosed before age 1 and many have early surgical intervention, usually before age 2.
The other main cause of pediatric HF is cardiomyopathy. At any given time point, cardiomyopathies affect at least 100,000 children worldwide. Recent studies indicate that the annual incidence of cardiomyopathy in the US, Australia, United Kingdom and Ireland are similar at approximately 1 per 100,000 children aged 18 or younger. The highest incidence is in children under 1 year of age. Dilated cardiomyopathy (usually diagnosed as idiopathic, familial, or myocarditis) is the most common type. In the United States, the annual incidence of dilated cardiomyopathy in children younger than 18 years is approximately 0.57 cases per 100,000 person-years. Hypertrophic cardiomyopathy due to familial isolated cardiomyopathy, an inborn error of metabolism, or a malformation syndrome is the next most common type. Cardiomyopathy can also be associated with muscular dystrophies such as Duchenne's muscular dystrophy and myotonic dystrophy. Other types of cardiomyopathy, including restrictive and arrhythmic cardiomyopathies are rarer. In 41-63% of the cardiomyopathy cases, the diagnosis was made during the first year of life, usually due to symptoms of HF. Morbidity and mortality of these diseases are high, and they are the most common cause of a heart transplant in children older than 1 year. Nearly 40% of children with a symptomatic cardiomyopathy either undergo heart transplantation or die within 2 years.
Remarkably, no trial with other drugs to date has demonstrated an outcome benefit of any pharmacotherapy in children with HF. In order to study the efficacy and safety of LCZ696 in children, there is a need for appropriate formulations in order to allow for pediatric studies and later pediatric treatment. Such formulations suitable for pediatric patients might also be suitable for other patients encountering problems with swallowing e.g. as a result of a disease or because of age or for psychological reasons,
Liquid dosage forms would allow for such individualized and easy to swallow delivery to patients—however, the chemical and physical stability and thus storage and transport of LCZ696 as mentioned, in particular the stability of the complex and especially of the prodrug sacubitril, may be hampered in liquids, the excipient tolerability may cause limitations, and taste considerations may make it difficult to supply drugs in dissolved or dispersed form in liquid formulations.
Normal solid oral dosage forms, that is, tablets and capsules for adults patients and/or patients where the standard adult dosage is to be administered, on the other hand, allow for less swallowability and dosing flexibility.
Small particle solid dosage forms, like powders, granules, agglomerates or pellets (e.g. resulting from fluid bed or other manufacturing processes), small capsules or uncoated tablets, would in principle allow to meet the dosage flexibility requirements—however, taste masking issue considerations apply to most of these variants, and it may be difficult to implement them if administration together with food is considered which allows to make the ingestion of the drugs more attractive and palatable for children and other patients.
LCZ696 as currently marketed (Tradename ENTRESTO™) is available in an oral dosage form as immediate release film-coated tablets of 200, 100 and 50 mg. This formulation does not fulfill the requirements of a pediatric formulation in terms of strength, dosing flexibility, patient acceptability (e.g. swallow ability) and size.
Also the physical-chemical properties, especially the stability of the prodrug sacubitril, and to a smaller extent the taste of the drug substance precludes the development of a liquid oral formulation which is standard of care for children.
A dosage form sometimes considered for pediatric use are formulations in form of minitablets, which may be provided with or without small amount of soft food, e.g. pudding or apple sauce. However, due to the very small size of these tablets of a few mg, the tablet manufacturing process with uniformity of content at the individual mini-tablet level such as that described in WO 2010/086312 can be extremely difficult. Further, not all of the pharmacopoeia methods established for pharmaceuticals are applicable for minitablets. So far mini-tablets are not described in any pharmacopoeial monographs.
In addition, due to the chemical nature of LCZ696 as a salt complex a premature release and dissolution of the drug when mixed with food should be prevented, whilst still allowing an immediate release profile upon ingestion.
In particular, the release profile of a pediatric formulation—in the appropriate overall dosage—should also show bioequivalence to the already available film tablets of LCZ696 in dosage strengths of 50 mg, 100 mg and 200 mg.
It is, therefore, an unmet need to develop and provide a pediatric formulation of LCZ696 that addresses the deficiencies of the marketed film-coated tablet in terms of a pediatric application, whereby said formulation has the size, dosing flexibility, acceptance and palatability desirable for an application in children and other patients as mentioned above while maintaining bioavailability comparable to the marketed drug product.